Methods for the preparation of sphingosine 1-phosphate receptor modulators and solid forme thereof

Abstract

The present invention relates to process for preparation of 1-(4-{1-[(E)-4-cyclohexyl-3-trifluoromethyl-benzyloxy imino]ethyl}-2-ethyl-benzyl)-azetidine-3-carboxylic acid, intermediates, salts and solid forms thereof to pharmaceutical compositions comprising the salts and solid forms and to use of said compositions for the treatment of multiple sclerosis, particularly secondary progressive multiple sclerosis.

1 - 65 . (canceled) 
     
     
         66 . A Siponimod adipic acid co-crystal, or a solvate or hydrate, and premixes thereof. 
     
     
         67 . The Siponimod adipic acid co-crystal according to  claim 66 , wherein the mole ratio of Siponimod to adipic acid is ranging from 1:0.25 to 1:1.2. 
     
     
         68 . The Siponimod adipic acid co-crystal according to  claim 66 , wherein the co-crystal has an XRD pattern comprising peaks at 6.50, 16.79, and 21.85±0.2° 2θ. 
     
     
         69 . The Siponimod adipic acid co-crystal according to  claim 66  in a substantially crystalline Form. 
     
     
         70 . A process for preparing Siponimod adipic acid co-crystal according to  claim 66 , the process comprising:
 a) dissolving Siponimod and adipic acid in a first organic solvent at a temperature of 25° C. to a reflux temperature of the first organic solvent;   b) removing the first organic solvent to produce a residue;   c) stirring the residue in a second organic solvent for at least 1 hour to 30 hours at 25-30° C. to produce a precipitate of the Siponimod adipic acid co-crystal;   d) isolating the precipitate of the Siponimod adipic acid co-crystal; and   e) drying the isolated precipitate at 30-60° C. for at least 1 hour to 10 hours.   
     
     
         71 . A process according to  claim 70 , wherein the Siponimod is in a polymorphic form or in a mixture of polymorphic forms. 
     
     
         72 . A process according to  claim 70 , wherein the first organic solvent is selected from the group comprising of C1 to C5 alcohols; nitriles; C1 to C6 halogenated hydrocarbonss; C6 to C14 aromatic hydrocarbons, C2 to C7 esters; C4 to C7 ethers; cyclic ether; aromatic ethers; DMF, DMSO, and mixtures thereof. 
     
     
         73 . A process according to  claim 70 , wherein the first organic solvent is selected from the group comprising of methanol, ethanol, isopropanol, t-butanol, acetonitrile, propionitrile, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, toluene, xylene, ethylbenzene, propylbenzene, butylbenzene, trimethylbenzene, tetramethylbenzene, cyclohexylbenzene, ethyl acetate, methyl acetate, isopropyl acetate, dimethyl ether, diethyl ether, ethyl methyl ether, tetrahydrofuran, 1,4-dioxane, diphenyl ether, DMF, DMSO, and mixtures thereof. 
     
     
         74 . A process for preparing Siponimod of Formula I: 
       
         
           
           
               
               
           
         
       
       which comprises:
 converting a compound of Formula XI: 
 
       
         
           
           
               
               
           
         
         wherein R1 is a C1-C4 alkyl group, to Siponimod of Formula I. 
       
     
     
         75 . The process according to  claim 74 , further comprising converting the Siponimod to a pharmaceutically acceptable salt thereof. 
     
     
         76 . The process according to  claim 74 , further comprising converting the Siponimod to a Siponimod adipic acid co-crystal. 
     
     
         77 . The process according to  claim 74 , wherein converting the compound of Formula XI comprises:
 reacting the compound of Formula XI with a compound of Formula IX or a salt thereof:   
       
         
           
           
               
               
           
         
       
       in the presence of a solvent to provide a compound of Formula X or a salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein R1 is the C1-C4 alkyl group; and
 hydrolyzing the compound of Formula X or the salt thereof in the presence of an acid or a base to provide the Siponimod of Formula I. 
 
     
     
         78 . The process according to  claim 74 , wherein the compound of Formula XI is prepared by
 i) reacting a compound of Formula XIII:   
       
         
           
           
               
               
           
         
         
           wherein R2 is a leaving group selected from the group consisting of alkyl sulfonyl, aryl sulfonyl, and acetyl, with a compound of Formula XII: 
         
       
       
         
           
           
               
               
           
         
         
           wherein R1 is the C1-C4 alkyl group, in the presence of a first base and a first solvent to provide the compound of Formula XI; or 
         
         ii) reacting a compound of Formula VI 
       
       
         
           
           
               
               
           
         
         
           wherein X 2  is a leaving group selected from the group consisting of chloro, bromo, and iodo, with the compound of Formula XII in the presence of a second base and a second solvent, to provide the compound of Formula XI. 
         
       
     
     
         79 . The process according to  claim 78 , wherein the compound of Formula XIII is prepared by reacting a compound of Formula VII: 
       
         
           
           
               
               
           
         
         with a protecting group to provide the compound of Formula XIII. 
       
     
     
         80 . The process according to  claim 77 , wherein the compound of Formula IX or the salt thereof is prepared by reacting a compound of Formula II: 
       
         
           
           
               
               
           
         
         wherein X 1  is a leaving group selected from the group consisting of bromo, chloro, iodo, and fluoro, with n-hydroxy phthalimide of Formula XV 
       
       
         
           
           
               
               
           
         
         in the presence of a second base and a second solvent to provide a compound of Formula XIV 
       
       
         
           
           
               
               
           
         
         reacting the compound of Formula XIV with hydrazine or a salt thereof in the presence of a third solvent to provide the compound of Formula IX; and optionally 
         converting the compound of Formula IX to the salt thereof. 
       
     
     
         81 . An intermediate for preparing Siponimod, wherein the intermediate is:
 a compound of Formula VI:   
       
         
           
           
               
               
           
         
       
       wherein X 2  is a leaving group selected from the group consisting of chloro, bromo, and iodo;
 a compound of Formula XI: 
 
       
         
           
           
               
               
           
         
       
       wherein R1 is C1-C4 alkyl group; or
 a compound of Formula IX or a salt thereof: 
 
       
         
           
           
               
               
           
         
       
     
     
         82 . The intermediate for preparing Siponimod according to  claim 81 , wherein the intermediate is the compound of Formula VI. 
     
     
         83 . The intermediate for preparing Siponimod according to  claim 81 , wherein the intermediate is the compound of Formula XI. 
     
     
         84 . The intermediate for preparing Siponimod according to  claim 81 , wherein the intermediate is the compound of Formula IX. 
     
     
         85 . A pharmaceutical composition, comprising the Siponimod adipic acid co-crystal according to  claim 66 , and one or more pharmaceutically acceptable excipients. 
     
     
         86 . A method of treating a relapsing form of multiple sclerosis in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of the Siponimod adipic acid co-crystal according to  claim 66 .